Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, thus maintaining control over cellular function. A partial list of such kinases includes Akt, Axl, Aurora A, Aurora B, Lck, Fyn, Lyn, Yes, dyrk2, epha2, fgfr3, vegfr3, igf1r, IKK2, JNK3, Vegfr2, MEK1, MET, Ron, Rsk1, CHK1, P70s6K, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt3, Flt1, PDK1 and Erk.
Abnormal cellular responses triggered by protein kinase-mediated events produce a variety of diseases. These include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Small molecule inhibitors of protein kinases like the Aurora kinases have been reported recently, but their effect on cytokinesis has yet to be investigated in detail. The Aurora family of conserved serine/threonine kinases perform essential functions during cell division. The three mammalian paralogues, Aurora A, B and C, are very similar in sequence, but differ significantly in their localization, function, substrates and regulatory partners. One highly selective and potent small-molecule inhibitor of the Aurora kinases, VX-680, blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types (Harrington E A, et al., Natl. J. Med., (2004) 10: 262-267). Another novel cell cycle inhibitor, JNJ-7706621, showed potent inhibition of several cyclin-dependent kinases (CDKs) and Aurora kinases, and selectively blocked proliferation of tumor cells of various origins (Emanuel S., et al., Cancer Res., 2005, 65:9038-9046). Additional cellular effects due to inhibition of Aurora kinases included endoreduplication and inhibition of histone H3 phosphorylation.
Aurora kinase inhibitors also have been identified by Hauf et al. (J. Cell. Biol., 2003, 161:281-294), who described the indolinone (Hesperadin) as an inhibitor of Aurora B that causes cells to enter anaphase with monooriented chromosomes; and Ditchfield et al. (J. Cell. Biol., 2003, 161:267-280) who disclosed ZM447439 ((4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy) quinazoline), an Aurora kinase inhibitor that interferes with chromosome alignment, segregation, and cytokinesis.
Aprea AB described 9H-carbazole derivatives that inhibit tumor cell growth by disrupting the interaction between the wildtype p53 tumor suppressor gene and HDM2, an oncogene protein, thereby restoring the ability of p53 to induce apoptosis via protein kinase signal transduction (WO 2004/035580 A1).
Takeda Pharmaceuticals Co., Ltd., disclosed pyrido-indole derivatives that are inhibitors of tyrosine kinases and cyclin-dependent kinases, and so are useful as antitumor, antibacterial and anti-viral agents (WO 2008/016184).
However, the need exists for a protein kinase inhibitor that is capable of inhibiting, modulating and/or regulating signal transduction by aberrant protein kinases, thereby effectively treating proliferative diseases such as cancers and cardiovascular, neurodegenerative, inflammatory, and endocrine-related diseases. It is also desirable for this protein kinase inhibitor to be useful in combination therapies for disease treatment and as a diagnostic tool.
These compounds of the present invention and pharmaceutical compositions comprising them are presented either individually or in kit form. Included in this invention also are processes for preparing the compounds that actively modulate or inhibit unregulated protein kinase activity.
Additional objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.